Rescue Agent Research Articles

Plerixafor Successfully Rescues Poor Mobilizers Resulting in Adequate CD34 Cell Numbers However Stem Cell Products Yield Lower Numbers of CFU/CD34 and Delayed Neutrophil Engraftment

Background: The CXCR4 inhibitor plerixafor was studied as a rescue agent in the setting of poor chemotherapy/filgrastim mobilization in a phase II trial of adults with lymphoma and myeloma who underwent a peripheral hematopoietic stem cell (HSC) mobilization prior to autologous transplant (ASCT) (NCT01037517). Given the wide range of expression of CD34 in myeloid precursors we were interested in the quality of the CD34 positive cells that were collected to proceed to transplant in poor mobilizers. Amongst a population of poor mobilizers would the CD34+ population contain cells of a more differentiated phenotype or express different proportions of homing receptors as CD34 cells collected from patients who mobilized easily?Methods: From 2009 to 2012 sequential adult patients with a diagnosis of lymphoma or multiple myeloma undergoing chemo-mobilization in preparation for autologous stem cell collection were enrolled on a phase II study to examine a strategy of plerixafor rescue in the setting of poor mobilization. Plerixafor (240 mcg/kg sc X 1) was administered on the evening prior to planned apheresis in subjects with a post nadir white blood cell count >1 X109/L and a peripheral blood [CD34] ≤ 10x106/L on the day prior to planned collection. Participants proceeded to stem cell apheresis the next day if their peripheral blood CD34 > 10x106/L. An aliquot from the mobilized product was analyzed for CD34+ cell subsets using markers of stemness ( CD33-, CD90, CD133 , CD166) and homing (CD26, CD49F, CD184) Differences between the groups are reported as means ±standard deviation and compared by two tailed t-tests.Results: 46/48 subjects were successfully mobilized in one day (HSC collection of >2 x 106 CD34+ cells/kg): 38 pts were not administered plerixafor (good mobilizer) and 8 pts were administered plerixafor (plerixafor rescue). The two participants not able to mobilize with plerixafor had evidence of progression of underlying disease within 2 weeks of attempted mobilization. Forty four participants (6/8 plerixafor and 38/38 good mobilizers) underwent ASCT. Median time to platelet engraftment was similar between good mobilizers (12 d, range 9-22d) and the plerixafor rescue group (13 d, range 12-13 d). The median time to neutrophil engraftment was prolonged in the plerixafor rescue group (23 d, range 17-67d) compared to good mobilizers (17 d, range 10-31d). CD34 content/kg of the apheresis product collected was similar between groups (good mobilizer 11.6±7.9 versus the plerixafor rescue group 6.4±4.6 p = 0.1). Subset analysis of CD34 positive cells in the products showed comparable expression of markers associated with more immature HSC progenitors but fewer CFU per CD34 positive cell plated. Homing receptors on the CD34 positive cells were similar despite the use of a CXCR4 inhibitor in the poor mobilizers. (See table) TableGood mobilizer N= 38 (Mean % ± SD)Plerixafor rescue N= 8 (Mean % ± SD)P valueStemmness MarkersCD90+ (Thy-1)24.4±12.730.6±19.30.3CD133+ (prominin1)59.1 ± 12.959.1 ± 16.80.9CD166+ (ALCAM)5.7±3.36.6±5.10.5CD33- (Siglec-3)80.6±3.369.8±13.10.01CFU/105 CD34+ cells1015±799276±3160.02Homing MarkersCD26 (dipeptidyl peptidase-4)5.4±410.4±13.30.05CD49F (VLA4)8.5±7.96.8±9.70.6CD184 (CXCR4)16.2±20.517.7±9.70.8Discussion: Plerixafor used to rescue patients at risk of poor mobilization resulted in collection of adequate numbers of CD34+ cells for transplantation and allowed ASCT in a majority of poor mobilizers in our series. Delayed neutrophil recovery, was seen in the poor mobilizer cohort. We did not see a skewing of the CD34+ cells in the products from poor mobilizers to a more mature phenotype but did find lower clonogenic potency with fewer CFU generated/CD34 cells plated. DisclosuresOff Label Use: Plerixafor used as initial mobilization strategy in autologous stem cell mobilization.

Abstract 31: Li-Fraumeni syndrome patient-derived LFS50 progression cell series: An experimental model for breast cancer prevention research

Abstract Background: Invasive cancer can be prevented or delayed in healthy but high-risk individuals; however, its prevention is a challenge partly due to (i) the lack of preclinical models that represent high-risk individuals in mechanistic in vitro studies and (ii) the difficulty in rational selection of novel targets and agents with a favorable risk to benefit ratio. Preclinical cell line models developed from high-risk, non-malignant breast tissue of women genetically predisposed to breast cancer can be a renewable resource for in vitro exploratory and cancer prevention studies. Toward this goal, contralateral breast tissue of a Li-Fraumeni syndrome (LFS) patient (patient 50 with a germline TP53 [M133T] mutation) undergoing breast cancer surgery was used to generate human mammary epithelial (HME) LFS progression series. This HME LFS50 series comprises of distinct pre-immortal (HME50), spontaneously immortalized (HME50-5E), hTERT-immortalized (HME50hTERT), HrasV12-transformed/pre-invasive (HME50hTR) and tumorigenic (HMET) cell lines and can be used to model different stages of breast cancer. Methods and Results: We have characterized the HME LFS50 cell lines in vitro as monolayers, 3D cultures, and by bioinformatics approach. Gene expression signatures of LFS50 series cells were profiled using HG-U133_Plus_2 Affymetrix chips, principal component analyses (PCA), and hierarchical clustering. Using the TNBCtype subtyping tool, we aligned LFS50 cell lines to triple negative breast cancer (TNBC) signatures that classified each of LFS50 cell lines as a different TNBC subtype model, suggesting that each HME LFS50 cell line would respond differentially to different chemotherapeutic agents. Furthermore, using Ingenuity Pathway Analysis (IPATM) we identified the most differentially expressed genes and canonical pathways that also support the TNBC subtyping results and provide rational targeting for chemoprevention studies. We determined the effects of p53 rescue agents (e.g., PRIMA-1) and chemopreventive agents such as epigallocatechin-3-galate and resveratrol, and found that tumorigenic HMET cells were most sensitive to these agents as compared to non-malignant HME50-hTERT and MCF10A controls. In addition, anchorage-independent growth could be prevented by chemopreventive agents for the HME50hTR pre-invasive cells. Finally, as a proof-of-principle for drug targeting, treatment of the LFS50 series with PRIMA-1 using 3D cultures resulted in a reduction in acini size of the pre-malignant and tumorigenic LFS50 cells (p<0.05). Conclusion: Each of the HME LFS50 cell lines exhibited distinct growth characteristics in monolayer as well as in 3D cultures, with differential gene expression profiles that can model different stages of breast cancer and provide rational targeting for chemoprevention studies. The use of well-characterized, high-risk patient-derived and physiologically relevant 3D preclinical models in conjunction with genomic profiling can potentially guide the development of safer and more effective chemopreventive approaches. Citation Format: Amruta R. Phatak, Brittney-Shea Herbert. Li-Fraumeni syndrome patient-derived LFS50 progression cell series: An experimental model for breast cancer prevention research. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 31. doi:10.1158/1538-7445.CANSUSC14-31

Abstract 1260: CP-31398 prevents the progression of oral squamous cell carcinomas from carcinogen-induced premalignant lesions

Abstract Head and neck squamous cell carcinoma (HNSCC) is an aggressive disease with a poor prognosis if not detected and treated at the early stages. P53 inactivation represents one of the most frequent molecular events in HNSCC. Here we studied a p53-reactivating small molecule, CP-31398, to prevent progression of premalignant oral squamous lesions to malignant HNSCC. We treated a panel of HNSCC cell lines with CP-31398 which resulted in a dose-dependent inhibition of cell proliferation as assessed by [3H]-Thymidine incorporation and cell cycle analysis, including induction of apoptotic cell death. These alterations were associated with an increased expression of the cell cycle inhibitor CDKN1A (p21WAF1) upon CP-31398 treatment. Interestingly, p53 function restoration by CP-31398 caused a marked decrease in activity of the PI3K/Akt/mTOR pathway, which is most frequently deregulated in HNSCC, and whose inhibition results in decreased tumorigenicity in multiple preclinical models systems. Indeed, CP-31398 treatment increased the expression of Sestrin 1/2 and REDD1; three well established p53-regulated genes that exert inhibitory activity over mTOR. Next, we evaluated the chemopreventive efficacy of CP-31398 in a 4-Nitroquinoline oxide (4NQO)-induced HNSCC mouse model that we have recently developed, which closely resembles development and progression of human HNSCC, including the induction of tp53 mutations as revealed by DNA sequencing. C57BL/6 mice were given 4NQO in the drinking water for a period of 14 weeks, during which all the animals developed an array of potential oral premalignant lesions. Upon 4NQO removal, mice were randomized into two groups receiving a control diet or a diet containing 250 ppm of CP-31398 for 8 weeks, in which the development and progression of tongue lesions were documented. At the conclusion of the study, 22 weeks, all mice were euthanized and subjected to full autopsies and histopathological evaluations. While 100% of the animals in the control group developed SCCs at the end of the study, there was a 70% reduction in the number of SCCs in the CP-31398- treated group. These findings suggest that the early, widespread alterations, of p53 during HNSCC progression can make this tumor type particularly vulnerable to intervention strategies, restoring p53 function by direct acting, p53 rescue agents. Hence, a large number of at risk patients exhibiting potential oral premalignant lesions harboring p53 mutations could benefit from the treatment with p53-reactivating small molecules such as CP-31398, which can also restrict the uncontrolled activation of the mTOR pathway. Overall, we present evidence of a novel chemopreventive intervention approach that exploits the emerging crosstalk between p53 and the mTOR pathways, including pharmacologic activation of mutant p53, individually and together with mTOR inhibitors, halting HNSCC progression. Citation Format: Lynn A. Vitale-Cross, Daniel Martin, Chinthalapally V. Rao, Levy Kopelovich, J. Silvio Gutkind. CP-31398 prevents the progression of oral squamous cell carcinomas from carcinogen-induced premalignant lesions. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1260. doi:10.1158/1538-7445.AM2014-1260

A density functional reactivity theory (DFRT) based approach to understand the interaction of cisplatin analogues with protecting agents.

In the present study some new insights are put into one of the major concern of cisplatin therapy and that is on the reduction of various cytotoxic and nephrotoxic side-effects of cisplatin analogues in cancer treatment. A better understanding of the interaction between different cisplatin analogues with various protecting agents can be achieved from the descriptors generated by density functional reactivity theory based comprehensive decomposition analysis of stabilization energy (Bagaria et al. in Phys Chem Chem Phys 11:8306-8315, 2009) scheme. Taking into account of three types of interactions i.e., of (1) Cisplatin analogues with DNA bases and base pairs (2) Cisplatin analogues with protecting agents and (3) Protecting agents with DNA bases, it is possible to develop a strategy (albeit qualitative) that suggests the best possible combinations of these drugs with protecting agents which can cause reduction in the toxic side-effects of cisplatin therapy. The sample set comprises of 96 pairs of cisplatin analogues and rescue agents and the generated data confirms the predictive power of the adopted strategy.

Inhalation of honey reduces airway inflammation and histopathological changes in a rabbit model of ovalbumin-induced chronic asthma.

BackgroundHoney is widely used in folk medicine to treat cough, fever, and inflammation. In this study, the effect of aerosolised honey on airway tissues in a rabbit model of ovalbumin (OVA)-induced asthma was investigated. The ability of honey to act either as a rescuing agent in alleviating asthma-related symptoms or as a preventive agent to preclude the occurrence of asthma was also assessed.MethodsForty New Zealand white rabbits were sensitized twice with mixture of OVA and aluminium hydroxide on days 1 and 14. Honey treatments were given from day 23 to day 25 at two different doses (25% (v/v) and 50% (v/v) of honey diluted in sterile phosphate buffer saline. In the aerosolised honey as a rescue agent group, animals were euthanized on day 28; for the preventive group, animals were further exposed to aerosolised OVA for 3 days starting from day 28 and euthanized on day 31. The effects of honey on inflammatory cell response, airway inflammation, and goblet cell hyperplasia were assessed for each animal.ResultsHistopathological analyses revealed that aerosolised honey resulted in structural changes of the epithelium, mucosa, and submucosal regions of the airway that caused by the induction with OVA. Treatment with aerosolised honey has reduced the number of airway inflammatory cells present in bronchoalveolar lavage fluid and inhibited the goblet cell hyperplasia.ConclusionIn this study, aerosolised honey was used to effectively treat and manage asthma in rabbits, and it could prove to be a promising treatment for asthma in humans. Future studies with a larger sample size and studies at the gene expression level are needed to better understand the mechanisms by which aerosolised honey reduces asthma symptoms.

Efficacy of just‐in‐time plerixafor rescue for Hodgkin's lymphoma patients with poor peripheral blood stem cell mobilization

Plerixafor is a Food and Drug Administration-approved agent for improving peripheral blood stem cell (PBSC) mobilization in filgrastim (granulocyte-colony-stimulating factor [G-CSF])-stimulated patients with multiple myeloma and non-Hodgkin's lymphoma. Limited information is available on its use in Hodgkin's lymphoma (HL) patients. We describe our experience with plerixafor as an immediate rescue agent in HL patients with poor PBSC mobilization. We retrospectively reviewed the collection data of 27 consecutive HL patients at our center in whom plerixafor was added to rescue a failing PBSC collection after G-CSF and chemotherapy (26) or G-CSF alone (1). Plerixafor was added in 11 patients due to peripheral blood (PB) CD34+ counts that persisted below the threshold (>10 × 10(6) /L) to initiate collection (median, 1.47 × 10(6) ; range 0 × 10(6) -6.28 × 10(6) /L) and in 16 patients due to low collection yields, who had a median yield of 0.33 × 10(6) (0.14 × 10(6) -0.65 × 10(6) ) CD34+ cells/kg on the last collection before plerixafor administration. After a median of 2 (range, 2-4) collections with plerixafor, the patients collected a median of 1.82 × 10(6) (0.52 × 10(6) -11.14 × 10(6) ) CD34+ cells/kg. The addition of plerixafor enabled 20 patients (74.1%) to reach the 2.0 × 10(6) CD34+ cells/kg minimum required for autologous stem cell transplantation (ASCT) during the same collection cycle. Subsequent remobilization in three patients with plerixafor enabled all three to reach this goal. Plerixafor can be used in HL patients with poor mobilization as a rescue agent and boosts mobilization sufficiently in most patients in the same collection attempt, thus not only permitting ASCT, but also avoiding remobilization and the associated costs, treatment delays, and patient inconvenience.

Nifedipine Compared With Atosiban for Treating Preterm Labor

OBJECTIVE To compare the tocolytic efficacy and tolerability of nifedipine with that of atosiban among pregnant women with preterm labor. METHODS Pregnant women admitted with preterm labor and intact membranes between 24 and 33 weeks 6 days of gestation, between January 2008 and December 2011, were randomly assigned to either atosiban or nifedipine treatment. Assigned treatment was planned for up to 48 hours. If progress was determined after 1 hour or more, a crossover of the study drugs was performed. The primary outcome was to estimate the tocolytic efficacy and tolerability profile that was assessed in terms of the proportion of women who were not delivered and did not require an alternate tocolytic agent within 48 hours. Secondary outcomes were gestational age at delivery and neonatal morbidity. RESULTS Seventy-five women in the nifedipine group and 70 in the atosiban group were included and analyzed. Baseline demographic and obstetric characteristics were comparable. Forty-eight (68.6%) women allocated to atosiban and 39 (52%) to nifedipine did not deliver and did not require an alternate agent at 48 hours respectively (P=.03). At 7 days from enrollment, 55 (78.6%) women allocated to atosiban and 67 (89.3%) to nifedipine remained undelivered with or without a rescue agent (P=.02). Mean gestational age at delivery was 35.2 (±3.0) and 36.4 (±2.8) weeks among the atosiban and nifedipine groups, respectively (P=.01). Mean birth weight and neonatal morbidity were comparable. CONCLUSIONS Atosiban has fewer failures within 48 hours. Nifedipine may be associated with a longer postponement of delivery. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, www.clinicaltrials.gov, NCT00599898.

P53 Protein Regulates Hsp90 ATPase Activity and Thereby Wnt Signaling by Modulating Aha1 Expression

The p53 tumor suppressor gene encodes a homotetrameric transcription factor which is activated in response to a variety of cellular stressors, including DNA damage and oncogene activation. p53 mutations occur in >50% of human cancers. Although p53 has been shown to regulate Wnt signaling, the underlying mechanisms are not well understood. Here we show that silencing p53 in colon cancer cells led to increased expression of Aha1, a co-chaperone of Hsp90. Heat shock factor-1 was important for mediating the changes in Aha1 levels. Increased Aha1 levels were associated with enhanced interactions with Hsp90, resulting in increased Hsp90 ATPase activity. Moreover, increased Hsp90 ATPase activity resulted in increased phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β), leading to enhanced expression of Wnt target genes. Significantly, levels of Aha1, Hsp90 ATPase activity, Akt, and GSK3β phosphorylation and expression of Wnt target genes were increased in the colons of p53-null as compared with p53 wild type mice. Using p53 heterozygous mutant epithelial cells from Li-Fraumeni syndrome patients, we show that a monoallelic mutation of p53 was sufficient to activate the Aha1/Hsp90 ATPase axis leading to stimulation of Wnt signaling and increased expression of Wnt target genes. Pharmacologic intervention with CP-31398, a p53 rescue agent, inhibited recruitment of Aha1 to Hsp90 and suppressed Wnt-mediated gene expression in colon cancer cells. Taken together, this study provides new insights into the mechanism by which p53 regulates Wnt signaling and raises the intriguing possibility that p53 status may affect the efficacy of anticancer therapies targeting Hsp90 ATPase.

Chemical rescue and inhibition studies to determine the role of Arg301 in phosphite dehydrogenase.

Phosphite dehydrogenase (PTDH) catalyzes the NAD+-dependent oxidation of phosphite to phosphate. This reaction requires the deprotonation of a water nucleophile for attack on phosphite. A crystal structure was recently solved that identified Arg301 as a potential base given its proximity and orientation to the substrates and a water molecule within the active site. Mutants of this residue showed its importance for efficient catalysis, with about a 100-fold loss in k cat and substantially increased K m,phosphite for the Ala mutant (R301A). The 2.35 Å resolution crystal structure of the R301A mutant with NAD+ bound shows that removal of the guanidine group renders the active site solvent exposed, suggesting the possibility of chemical rescue of activity. We show that the catalytic activity of this mutant is restored to near wild-type levels by the addition of exogenous guanidinium analogues; Brønsted analysis of the rates of chemical rescue suggests that protonation of the rescue reagent is complete in the transition state of the rate-limiting step. Kinetic isotope effects on the reaction in the presence of rescue agents show that hydride transfer remains at least partially rate-limiting, and inhibition experiments show that K i of sulfite with R301A is ∼400-fold increased compared to the parent enzyme, similar to the increase in K m for phosphite in this mutant. The results of our experiments indicate that Arg301 plays an important role in phosphite binding as well as catalysis, but that it is not likely to act as an active site base.

Multiagent-based ABC Algorithm for Dynamical Environment: Toward Cooperation among Autonomous Rescue Agents

Multiagent-based ABC Algorithm for Dynamical Environment: Toward Cooperation among Autonomous Rescue Agents

Adenosine amine congener as a cochlear rescue agent.

We have previously shown that adenosine amine congener (ADAC), a selective A1 adenosine receptor agonist, can ameliorate noise- and cisplatin-induced cochlear injury. Here we demonstrate the dose-dependent rescue effects of ADAC on noise-induced cochlear injury in a rat model and establish the time window for treatment. Methods. ADAC (25–300 μg/kg) was administered intraperitoneally to Wistar rats (8–10 weeks old) at intervals (6–72 hours) after exposure to traumatic noise (8–16 kHz, 110 dB sound pressure level, 2 hours). Hearing sensitivity was assessed using auditory brainstem responses (ABR) before and 12 days after noise exposure. Pharmacokinetic studies investigated ADAC concentrations in plasma after systemic (intravenous) administration. Results. ADAC was most effective in the first 24 hours after noise exposure at doses >50 μg/kg, providing up to 21 dB protection (averaged across 8–28 kHz). Pharmacokinetic studies demonstrated a short (5 min) half-life of ADAC in plasma after intravenous administration without detection of degradation products. Conclusion. Our data show that ADAC mitigates noise-induced hearing loss in a dose- and time-dependent manner, but further studies are required to establish its translation as a clinical otological treatment.

264: 10:12 CLA as an endothelial rescue agent: a novel dietary approach to preeclampsia therapy

264: 10:12 CLA as an endothelial rescue agent: a novel dietary approach to preeclampsia therapy

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Introduction: Utilization of magnetic resonance imaging (MRI) in children is on the rise. The majority of children require sedation for MRI. Choosing the correct drug that is short-acting, safe, and effective is important. Hypothesis: Pediatric patients receiving dexmedetomidine (DEX) for MRI sedation require additional rescue agents to maintain comparable sedation, and have longer recovery times when compared to propofol (PROP). Methods: A retrospective chart review of outpatient MRI sedations in patients aged 6 months to 21 years (ASA 1 or 2) from January to December 2011. Patients were sedated with DEX or PROP to achieve a sedation score of zero. DEX group was given IV bolus of 1.5 mcg/kg/min over 10 minutes followed by infusion at 1 mcg/kg/min. If needed, additional bolus of 0.5 mcg/kg was given to achieve sedation score of zero. PROP group were given IV bolus in 1mg/kg increments to achieve a sedation score of zero. They were then placed on an infusion of 100mcg/kg/min. The following parameters were measured: amount of rescue boluses needed to complete MRI, time to complete MRI, time to wake up, and time to discharge. Adverse events measured included bradycardia, incidence of apnea requiring BVM, and hypotension requiring IV bolus. Results: 208 charts (103 PROP, 105 DEX) were reviewed. Median age was 3.9 years. The majority of studies were brain MRI (78%). Forty five (42.9%) DEX patients required rescue boluses of PROP or midazolam to achieve a sedation score of zero. Only 9 (8.7%) PROP patients required rescue boluses of additional PROP (p<0.001). DEX patients had longer recovery times after sedation when compared to PROP patients (55 vs. 33 min, p<0.001). DEX patients took on average 20 minutes longer to be discharged after completion of MRI (p<0.001). 2 DEX patients were not able to complete MRI and required general anesthesia. All PROP patients completed MRI. There were no adverse events in either group. Conclusions: PROP provided superior sedation in regards to completion of MRI, shorter wake up times and time to discharge when compared to DEX.

Allogeneic Human Mesenchymal Stem Cell Therapy (Remestemcel-L, Prochymal) as a Rescue Agent for Severe Refractory Acute Graft-versus-Host Disease in Pediatric Patients

Severe steroid-refractory acute graft-versus-host disease (aGVHD) is related to significant mortality and morbidity after allogeneic stem cell transplantation. Early clinical trials of therapy with human mesenchymal stem cells (hMSCs) in pediatric patients with severe aGVHD resistant to multiple immunosuppressive agents showed promising results. In this study, we evaluated the risk/benefit profile of remestemcel-L (Prochymal), a third-party, off-the-shelf source of hMSCs, as a rescue agent for treatment-resistant aGVHD in pediatric patients. Children with grade B-D aGVHD failing steroids and, in most cases, other immunosuppressive agents were eligible for enrollment. Patients received 8 biweekly i.v. infusions of 2 × 106 hMSCs/kg for 4 weeks, with an additional 4 weekly infusions after day +28 for patients who achieved either a partial or mixed response. The enrolled patients compose a very challenging population with severe disease that was nonresponsive to the standard of care, with 88% of the patients experiencing severe aGVHD (grade C or D). Seventy-five patients (median age, 8 yr; 58.7% male; and 61.3% Caucasian) were treated in this study. Sixty-four patients (85.3%) had received an unrelated hematopoietic stem cell graft, and 28 patients (37.3%) had received a cord blood graft. At baseline, the distribution of aGVHD grades B, C, and D was 12.0%, 28.0%, and 60.0%, respectively. The median duration of aGVHD before enrollment was 30 d (range, 2 to 1639 d), and patients failed a median of 3 immunosuppressive agents. Organ involvement at baseline was 86.7% gastrointestinal, 54.7% skin, and 36.0% liver. Thirty-six patients (48.0%) had 2 organs involved, and 11 patients (14.7%) had all 3 organs involved. When stratified by aGVHD grade at baseline, the rate of overall response (complete and partial response) at day +28 was 66.7% for aGVHD grade B, 76.2% for grade C, and 53.3% for grade D. Overall response for individual organs at day +28 was 58.5% for the gastrointestinal system, 75.6% for skin, and 44.4% for liver. Collectively, overall response at day +28 for patients treated for severe refractory aGVHD was 61.3%, and this response was correlated with statistically significant improved survival at day +100 after hMSC infusion. Patients who responded to therapy by day +28 had a higher Kaplan-Meier estimated probability of 100-d survival compared with patients who did not respond (78.1% versus 31.0%; P < .001). Prochymal infusions were generally well tolerated, with no evidence of ectopic tissue formation.

3D APPLICATIONS IN DISASTER MITIGATION AND MANAGEMENT: CORE RESULTS OF DITAC PROJECT

Abstract. According to statistical data, natural disasters as well as the number of people affected by them are occurring with increasing frequency compared to the past. This situation is also seen in Europe Union; So, Strengthening the EU capacity to respond to Disasters is very important. This paper represents the baseline results of the FP-7 founded DITAC project, which aims to develop a holistic and highly structured curriculum for responders and strategic crisis managers. Up-to-date geospatial information is required in order to create an effective disaster response plan. Common sources for geospatial information such as Google Earth, GIS databases, and aerial surveys are frequently outdated, or insufficient. This limits the effectiveness of disaster planning. Disaster Management has become an issue of growing importance. Planning for and managing large scale emergencies is complex. The number of both victims and relief workers is large and the time pressure is extreme. Emergency response and triage systems with 2D user interfaces are currently under development and evaluation. Disasters present a number of spatially related problems and an overwhelming quantity of information. 3D user interfaces are well suited for intuitively solving basic emergency response tasks. Such tasks include commanding rescue agents and prioritizing the disaster victims according to the severity of their medical condition. Further, 3D UIs hold significant potential for improving the coordination of rescuers as well as their awareness of relief workers from other organizations. This paper describes the outline of a module in a Disaster Management Course related to 3D Applications in Disaster Mitigation and Management. By doing this, the paper describes the gaps in existing systems and solutions. Satellite imageries and digital elevation data of Turkey are investigated for detecting sites prone to natural hazards. Digital image processing methods used to enhance satellite data and to produce morphometric maps in order to contribute to the detection of causal factors related to landslides, local site conditions influencing and/or experiencing earthquake damage intensity or those of tsunami and storm surge hazard sites at the coasts.

Masitinib mesylate for metastatic and non‐resectable canine cutaneous mast cell tumours

Masitinib mesylate is a tyrosine kinase inhibitor approved for the treatment of gross, non-metastatic grade II and III canine mast cell tumours (MCTs). This study evaluated the use of masitinib as a frontline and rescue agent for metastatic and non-metastatic canine MCTs. Identification of toxicities and prognostic factors in these dogs was of secondary interest. Twenty-six dogs were included in this study. The overall response rate to masitinib was 50%. The median survival time for dogs that responded to masitinib was 630 days versus 137 days for dogs that did not respond (P = 0.0033). Toxicity was recorded in 61.5% of treated dogs, but the majority of adverse events were mild and self-limiting. Response to masitinib, not tumour grade, stage or location, was the most significant prognostic factor for survival in dogs with MCTs.

A phase II pilot study of fosaprepitant (F) for the rescue of acute nausea and vomiting with moderately (MEC) or highly emetogenic chemotherapy (HEC) in adults.

e20627^ Background: Patients receiving MEC or HEC continue to have breakthrough nausea and emesis despite antiemetic prophylaxis. Few trials have evaluated the efficacy of rescue antiemetics after failed prophylaxis. F, a prodrug of the neurokinin-1 antagonist (NK1a), aprepitant is FDA-approved for the prevention of acute and delayed nausea and vomiting associated with MEC and HEC. F’s safety and efficacy in the prophylactic setting make F an attractive potential rescue therapy. Methods: F 150mg was infused as the initial rescue agent in eligible patients receiving MEC or HEC who had either emesis or nausea despite guideline-based prophylaxis with a 5HT-3 antagonist and dexamethasone. The primary endpoint was improved nausea on a visual analogue scale (VAS) at 2 hours. Secondary endpoints included: VAS at 12 and 24 hrs, rescue medication use, emesis, nutritional intake, adverse events, and proof of the study design as a viable methodology. Results: Eleven adult patients, 6 males and 5 females, were treated per protocol and evaluable for the 24 hour study period. Chemotherapy regimens included HiDAC, R-CHOP, epirubicin/ifosfamide, EPOCH, R-ICE, 7+3, VAC, and HyperCVAD. 3 patients were treated for emesis and 8 for nausea. 91% of patients had improved nausea at 2 hrs, 100% at 12 hrs and 63.6% at 24 hrs. F prevented further emesis in 2 of 3 patients and no patient with initial nausea had subsequent emesis. 9 of 11 (81.8%) patients required additional rescue medication during the study period, mainly due to nausea. Appetite was improved in 8/11 patients. Food and fluid intake improved in 5/11. Adverse effects included headache 18%, dizziness 18%, hiccups 9%, indigestion 9%, and 1 case ifosfamide encephalopathy. The study design required greater than anticipated consented patients due to the success rates of standard antiemetic therapy. Conclusions: F improves breakthrough nausea and related symptoms, and may prevent further emesis but was suboptimal as a single agent in that the majority of patients required a second rescue agent within 24 hrs. Complete response, defined as no emesis and no rescue therapy, may be a more clinically relevant primary endpoint in future trial designs. Clinical trial information: NCT00939302.

Disaster Rescue Simulation based on Complex Adaptive Theory

Disaster rescue is one of the key measures of disaster reduction. The rescue process is a complex process with the characteristics of large scale, complicate structure, non-linear. It is hard to describe and analyze them with traditional methods. Based on complex adaptive theory, this paper analyzes the complex adaptation of the rescue process from seven features: aggregation, nonlinearity, mobility, diversity, tagging, internal model and building block. With the support of Repast platform, an agent-based model including rescue agents and victim agents was proposed. Moreover, two simulations with different parameters are employed to examine the feasibility of the model. As a result, the proposed model has been shown that it is efficient in dealing with the disaster rescue simulation and can provide the reference for making decisions. DOI: http://dx.doi.org/10.11591/telkomnika.v11i5.2467

α-Lipoic acid protects against arsenic trioxide-induced acute QT prolongation in anesthetized guinea pigs

Clinical use of arsenic trioxide (As2O3), which can induce the remission of relapsed or refractory acute promyelocytic leukemia, is often limited because of its cardiotoxicity. Symptoms of cardiotoxicity include acute cardiac conduction disturbances, such as QT prolongation. The present study was undertaken to evaluate the effects of α-lipoic acid (LA) on acute As2O3-induced ECG abnormalities (QTc interval prolongation) in anesthetized guinea pigs. Intravenous injection of As2O3 in guinea pigs caused QTc interval prolongation, which was significantly attenuated by co-treatment with LA (0.35, 3.5 and 35mg/kg) in a dose-dependent manner. In isolated guinea pig cardiomyocytes, the decrease in IKs current induced by As2O3 (1μM) was rapidly restored to the basal level by the addition of LA (10μM). Consistent with this finding, the As2O3-induced QTc interval prolongation was also improved rapidly by post-treatment with LA in guinea pigs. Electrospray ionization time-of-flight mass spectrometry analysis detected an expected peak of arsenic-LA complex in vitro, indicating that LA and As2O3 form a new compound in vivo. In addition, pre-treatment with a chelating agent, British anti-Lewisite (BAL, 3.5 or 35mg/kg), also attenuated the As2O3-induced QTc interval prolongation. In this study, co- and post-treatments with LA and pre-treatment with BAL ameliorated As2O3-induced acute QT prolongation in anesthetized guinea pigs. Because LA and probably BAL may bind to As2O3, these agents may exert protective effects through their chelating activity. Further studies are needed to determine whether LA is beneficial as a prophylactic or rescue agent for acute promyelocytic leukemia patients treated with As2O3.

Aerosolized Honey as a Regenerative Agent in Animal Model of Asthma

Asthma is a disease characterized by infiltration of inflammatory cells into lung tissue, excessive mucus production, chronic airway obstruction and airway hyperresponsiveness (1). Inhaled corticosteroid is a common therapy for asthma. However, prolonged usage of drug therapy may lead to several side effects (2). Honey has been extensively studied and claimed to be effective in treating cough and asthma. Honey nebulisation has been proven effective in treating upper respiratory disease (3). However, the effects of aerosolized honey in reducing asthma-related symptoms at the cellular level have not been studied. The aim of this study was to determine the effects of honey on histopathology of airways in rabbits induced to have chronic lung disease that mimicked the human condition of asthma. The effects of honey to act as both rescue and preventive agents in alleviating asthmatic symptoms were tested. In both rescue and preventive treatment groups, 12 New Zealand white rabbits (n=3) were sensitized via intraperitoneal (ip) injections of 0.1mg/ml ovalbumin (OVA) with 10mg/ml aluminium hydroxide (alum) at day 1 and day 14. Sterile phosphate buffer saline (PBS) was used to act as negative control. Following the ip injections for OVA-treated group (n=3) (positive control group), rabbits were exposed to OVA inhalation (10mg/ml) for 3 subsequent days starting from day 28 and euthanized at day 31. In negative control group, PBS was given in a similar manner as OVA-treated group. For rescue treatment group (n=3), following the ip injections, at day 23 until day 27, animals were treated with 25% of honey using aerosolisation technique followed by euthanasia at day 28. For preventive treatment group (n=3), following second ip injection with OVA, aerosolized honey was continuously given from day 23 until day 27. Subsequently, rabbits were further exposed to OVA inhalation for 3 days starting from day 28 until day 30 and euthanized on day 31. For each treatment, 2ml of honey was aerosolised for 20 min duration. Histopathological changes of the airways were determined using H&E and AB-PAS staining. A massive infiltration of eosinophils, lymphocytes and mononuclear cells were observed in OVA-treated animals. The airways also showed disruption of epithelium, goblet cell hyperplasia and thickened subepithelial smooth muscle layer, which are characteristic of asthma. Animals exposed to aerosolised honey, especially in the rescue group, showed reduction of these inflammatory changes. In conclusion, this study shows that aerosolised honey are effective in reducing asthma-related cellular changes in models of rabbit-induced chronic lung disease.